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Genotypic& phenotypic characterization of the HCV polymerase (NS5B) in HIV

基因型

基本信息

批准号：
8658112
负责人：
JASON T BLACKARD
金额：
$ 30.31万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-05-02 至 2018-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8658112
关键词：
AIDS/HIV problem Address Amino Acid Substitution Antiviral Agents Biochemical Biochemistry Chronic Hepatitis C Clinical Clinical Management Collaborations Data Development Disease Progression Drug resistance Epidemiologic Studies Epitopes Evolution Fibrosis Funding Genetic Genome HIV HIV therapy Hepatitis Hepatitis C Hepatitis C virus Immune Immune Targeting Immune response Immune system In Vitro Individual Infection Injecting drug user Life Liver diseases Medicine Mono-S Morbidity - disease rate Mutation National Institute of Drug Abuse Natural History New Agents Pathogenesis Patients Persons Polymerase Population Positioning Attribute Prevalence Property Proteins RNA RNA-Directed RNA Polymerase Reporting Research Resistance Risk Saints Structural Genes Structure Treatment outcome Universities Variant Viral Viral Load result Virus Virus Diseases Virus Replication Woman Work antiretroviral therapy college design fitness improved in vivo inhibitor/antagonist mortality novel pressure public health relevance research study resistance mutation treatment response viral RNA virus genetics

项目摘要

DESCRIPTION (provided by applicant): Co-infection with hepatitis C virus (HCV) has emerged as a major cause of morbidity and mortality for persons living with HIV/AIDS. Epidemiologic studies clearly indicate that HIV/HCV co-infection is associated with enhanced HCV replication, increased fibrosis, and the development of liver disease. HIV also increases quasispecies diversity of HCV structural genes. However, non-structural regions of the HCV genome such as NS5B are subject to distinct selection pressures - purifying selection necessary to preserve enzymatic functions critical for viral replication, drug resistance mutations, and/or compensatory mutations - compared to structural genome regions. Despite the growing importance of NS5B as an emerging target of HCV therapy, limited data are available regarding its genotypic variability and phenotypic properties in the absence of directly acting therapies. To address this substantial gap in our understanding of HCV replication and pathogenesis, we propose a comprehensive analysis of NS5B genotypic, phenotypic, and biochemical variability in two well-characterized populations with HCV and/or HIV co-infection. Such studies are critical to facilitate the rational design and utilization of novel HCV therapies and significantly improve the clinical management and overall survival of persons with chronic HCV infection.

描述(由申请人提供)：与丙型肝炎病毒(丙型肝炎病毒)混合感染已成为艾滋病毒/艾滋病患者发病和死亡的主要原因。流行病学研究清楚地表明，艾滋病毒/丙型肝炎病毒混合感染与丙型肝炎病毒复制增强、纤维化增加和肝病的发展有关。艾滋病毒还增加了丙型肝炎病毒结构基因的准种多样性。然而，与结构基因组区域相比，丙型肝炎病毒基因组的非结构区域，如NS5B，受到不同的选择压力--纯化选择对于保持对病毒复制、耐药性突变和/或补偿性突变至关重要的酶功能是必要的。尽管NS5B作为丙型肝炎病毒治疗的一个新兴靶点日益重要，但在缺乏直接作用的治疗方法的情况下，关于其基因变异性和表型特性的数据有限。至为了解决我们对丙型肝炎病毒复制和发病机制的理解上的这一重大差距，我们建议对两个具有良好特征的丙型肝炎病毒和/或艾滋病病毒混合感染人群的NS5B基因、表型和生化变异进行全面分析。这些研究对于促进丙型肝炎病毒新疗法的合理设计和使用，以及显著改善慢性丙型肝炎感染者的临床管理和总体生存至关重要。